Alcohol abuse and alcoholism (alcohol use disorders) are significant public health issues and represent one of the largest public health problems. In the United States alone, alcohol use disorders affect about 14 million people, costing approximately $184 billion a year due to lost wages, legal and medical costs from associated injuries and liver, cardiac, neoplastic, or infectious diseases. Even though elaborate psychosocial and psychotherapeutic approaches for the treatment of alcoholism have been developed, relapse rates after long- term treatment of alcoholism clearly exceed 50% and may occur even after decades of abstinence. So far, only three drugs have been approved for treatment in the United States: disulfuram, naltrexone and acamprosate. Disulfuram is useful for the short-term treatment of highly motivated and compliant patients, but there is no evidence it is effective in long-term therapy and it carries a risk of significant liver, cardiac, and nervous system toxicity if taken with alcohol. For both naltrexone and acamprosate, which cause a variety of side effects, compliance is generally low, with only about half of patients completing treatment with either drug. Clearly, there is an unmet need to develop more effective compounds with novel molecular targets due to lack of single 'unifying' neurobiological theory to explain basic mechanisms of alcohol use disorders and, some different drugs with different targets have been tested. The current proposal is focused on the development of a novel oral compound that acts as isoform specific inhibitor of the enzyme protein kinase C epsilon (PKCe), which has been demonstrated an ideal target for alcohol use disorders. The overall objective of this SBIR Phase II Competing Renewal research plan is to advance the positive results of our prior Phase II program to enable development of the first oral- and CNS-active and isoform-selective PKCe inhibitor, VMD-2202 through an Investigational New Drug (IND) application to the FDA for the treatment of alcohol use disorders. VMD-2202 is orally effective reducing excessive alcohol intake in established animal model without affecting water intake. It has reasonable in vivo safety profile without sedation or motor incoordination, a CNS side effect often seen in many CNS drugs. We now propose a three-year preclinical drug development project through IND submission to the FDA, under NIH SBIR Phase II Competing Renewal Awards at NIAAA. In the first year of this proposal, we intend to further test therapeutic potential of VMD-2202 in various phases of alcohol uses disorders with a battery of established preclinical rodent models. In parallel, we will perform further lead optimization on the VMD-2202-based novel chemical scaffold to select another lead analog compound as the back-up entity. In the second and third year, we will conduct IND-enabling studies for one chosen development candidate advanced from the first year, including evaluation of the safety and pharmacokinetic profile, GMP manufacture and GLP safety pharmacology and toxicology studies in two animal species, which are necessary for an IND application to the FDA. At the end of the third year of this grant project, we will write and assemble an IND package and submit it to the FDA. If the FDA accepts the IND application, we will shortly thereafter begin the Phase I human clinical trials.